Amperometric biosensors are capable of measuring glucose on a continuous basis in the subcutaneous space and the intravascular space of mammals. To the extent that such sensors utilize glucose oxidase and do not utilize an electron mediator, they use one dioxygen molecule for each molecule of glucose that is acted upon by the enzyme. Throughout the range of glucose concentrations, one oxygen molecule must accompany each glucose molecule in the enzyme layer of the sensor, in order for the glucose sensing reaction to occur. Such a reaction yields hydrogen peroxide, which, when oxidized at an indicating electrode, generates an electrical current.
When mammalian physiology is taken into account, it is clear that unless specific design precautions are taken, a glucose sensor may not respond adequately in an elevated glucose range, or in a low-oxygen (“hypoxia”) range. It is well-known that the concentration of glucose in subcutaneous tissue is much greater than that of oxygen. In fact, the concentration of glucose may be several hundred times greater than that of oxygen, depending on specific physiological circumstances. It may be appreciated that if an outer membrane of a membrane-biosensor system does not allow a sufficient quantity of oxygen molecules into an underlying enzyme layer, the sensor output may not be proportional to the prevailing glucose concentration in the tissue. For example, at elevated glucose concentrations, a membrane with insufficient oxygen permeability (or too high a glucose permeability) may generate a current that plateaus as the glucose concentration continues to rise above normal concentrations. Often, in persons with diabetes mellitus, glucose concentrations may rise to very high concentrations, even exceeding 400 mg/dl in blood.
The problem of insufficient oxygen in conjunction with high glucose concentrations has been termed the oxygen deficit problem. A factor that contributes to the oxygen deficit problem is the fact that subcutaneous oxygen concentrations are much lower than blood oxygen concentrations. One study showed that in rabbits, the subcutaneous oxygen tension averaged only 30-50 Torr (Ward, W. K., Wood, M. D, Slobodzian, E. P., Continuous amperometric monitoring of subcutaneous oxygen in rabbit by telemetry, Vol. 26, page 158-67, Journal of Medical Engineering and Technology, 2002), and oxygen tension in mammalian blood is higher than this.
With regard to glucose oxidase-based biosensors that use an oxygen molecule for each glucose molecule, there is an oxygen deficit in normal mammals that reduces their measurement accuracy. It is important to note that the oxygen deficit problem may be even greater in persons with respiratory problems and in persons who live at high altitude. For example, individuals with severe asthma (reactive airways disease), chronic obstructive pulmonary disease (emphysema or chronic bronchitis), pneumonia, or hypoventilation from any cause (e.g. neurological conditions, musculoskeletal problems or drug-induced hypoventilation) often have abnormally low concentrations of oxygen in their blood and in their subcutaneous tissue. It may be seen that this problem of an oxygen deficit, which is significant in normal individuals, may be even greater in certain individuals or in certain environments. Particularly in a hospital setting, it is common to encounter patients who have one or more of the conditions that predispose a patient to low oxygen concentration in the blood. In addition, persons who live at high altitude have relatively low concentrations of oxygen in blood and tissue. A normal person living or vacationing in Leadville, Colo. would likely have a partial pressure of oxygen in arterial blood (paO2) of approximately 55-65 Torr whereas the same individual living at sea level would have a paO2 of 95-100 Torr.
In summary, with regard to amperometric sensors that use equimolar amounts of oxygen and glucose, there is a problem of an oxygen deficit in normal individuals. In persons located at a high altitude or who suffer from certain medical conditions, the problem may be even greater.
The problem of the oxygen deficit has been recognized by inventors in the field of amperometric glucose sensors. Shichiri disclosed a homogeneous hydrophobic membrane, but such a membrane typically does not provide the optimal balance between oxygen and glucose transport, see Glycaemic Control in Pancreatectomized dogs with a Wearable Artificial Endocrine Pancreas, published in Diabetologia 24, 179-84, 1983. Furthermore, such a membrane does not provide for tailoring the properties of the membrane by varying the preponderance of hydrophilic and hydrophobic moieties.
Other attempts have been made to measure glucose using a subcutaneous sensor, but the membranes used in such sensors typically take up substantial amounts of glucose. For this reason, these membranes are likely to plateau in their response to high concentrations of glucose when used in a setting of low tissue oxygen.
The issue of polymer strength is also important for sensor membranes that are placed in mammals. Various patents disclose methods of engineering materials to have particular permselectivities, see U.S. Pat. Nos. 5,428,123; 5,589,563; and 5,756,632, the disclosures of which are hereby incorporated by reference in their entirety. However, when efforts were made to use these materials in an indwelling glucose sensor application, it was found that the requirement for high oxygen and glucose permeability was at conflict with the requirement for structural strength and integrity desired for exposure to an oxidative environment. More specifically, it was found that when the material was made sufficiently oxygen permeable, it became too weak and tended to break apart on the sensor after being present in the body's interstitial fluid for more than a few hours.
Within biological solutions such as blood or interstitial fluid there exist a number of reactive materials and enzymes that may bring about cleavage of the polymer's molecular chains and thus result in loss of membrane strength and integrity. Some of the reactive materials and enzymes that may bring about polymer degradation and cleavage include small molecules such as superoxide (O2−), acids, and enzymes such as proteases and oxidases that react with the various types of linkages in the polymer. This loss of membrane or fiber integrity may be deleterious to applications which depend on the permselectivity of the polymeric material and the exclusion of solids and larger biological molecules, such as the detection of the levels of glucose within the body fluids of a living human body.